EP3607947A1 - Combination of tafia inhibitor with plasminogen activator - Google Patents

Combination of tafia inhibitor with plasminogen activator Download PDF

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Publication number
EP3607947A1
EP3607947A1 EP19180386.5A EP19180386A EP3607947A1 EP 3607947 A1 EP3607947 A1 EP 3607947A1 EP 19180386 A EP19180386 A EP 19180386A EP 3607947 A1 EP3607947 A1 EP 3607947A1
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EP
European Patent Office
Prior art keywords
compound
acceptable salt
pharmacologically acceptable
embolism
thrombosis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19180386.5A
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German (de)
English (en)
French (fr)
Inventor
Kengo Noguchi
Yusuke Ito
Naoko EDO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
Original Assignee
Daiichi Sankyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Sankyo Co Ltd filed Critical Daiichi Sankyo Co Ltd
Publication of EP3607947A1 publication Critical patent/EP3607947A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a pharmaceutical composition for treatment or prevention of thrombosis or embolism or a sequela thereof, comprising a particular TAFIa inhibitor and a plasminogen activator, the TAFIa inhibitor being administered in combination with the plasminogen activator, and a method for treating or preventing thrombosis or embolism or a sequela thereof, comprising administering a particular TAFIa inhibitor in combination with a plasminogen activator to a warm-blooded animal.
  • Thrombolytic therapy which involves reopening blood vessels using a plasminogen activator is effective for the treatment of thrombosis or embolism such as acute myocardial infarction, acute-stage cerebral infarction, cardiogenic embolus, or peripheral arterial or venous occlusion.
  • this therapy disadvantageously causes adverse reaction such as hemorrhage.
  • a sufficient amount of the plasminogen activator may not be able to be administered, and a therapeutic effect may not be exerted due to insufficient lysis of thrombus or embolus.
  • a treatment method for effectively lysing thrombus or embolus without increasing the dose of the plasminogen activator or by decreasing the dose thereof.
  • Non Patent Literature 1 and 2 describe an antithrombotic effect brought about by the combined use of a compound that exhibits activated thrombin-activatable fibrinolysis inhibitor (hereinafter, referred to as "TAFIa”) inhibitory activity, and a tissue plasminogen activator (hereinafter, referred to as "t-PA").
  • TAFIa activated thrombin-activatable fibrinolysis inhibitor
  • t-PA tissue plasminogen activator
  • Patent Literature 1 discloses a compound group that exhibits TAFIa inhibitory activity, and shows that this compound group is useful as a therapeutic drug for thrombosis or embolism. This literature also states that the compound group may be used in combination with an anticoagulant, an antiplatelet drug, or an enzyme related to fibrinolysis, etc.
  • Patent Literature 1 International Publication No. WO 2011/115064
  • An object of the present invention is to provide a pharmaceutical composition for treatment or prevention of thrombosis or embolism or a sequela thereof, comprising a particular TAFIa inhibitor and a plasminogen activator, the TAFIa inhibitor being administered in combination with the plasminogen activator, and a method for treating or preventing thrombosis or embolism or a sequela thereof, comprising administering a particular TAFIa inhibitor in combination with a plasminogen activator to a warm-blooded animal.
  • the present inventors have conducted studies with the aim of investigating an effect brought about by the combined use of a TAFIa inhibitor and a plasminogen activator. As a result, the present inventors have found that synergistic fibrinolytic activity is exerted by administering a particular TAFIa inhibitor in combination with a plasminogen activator.
  • the present invention encompasses the following aspects.
  • the present invention can provide a pharmaceutical composition for treatment or prevention of thrombosis or embolism or a sequela thereof, comprising a particular TAFIa inhibitor and a plasminogen activator, the TAFIa inhibitor being administered in combination with the plasminogen activator, and a method for treating or preventing thrombosis or embolism or a sequela thereof, comprising administering a particular TAFIa inhibitor in combination with a plasminogen activator to a warm-blooded animal.
  • the compound represented by the formula (I): used in the present invention can be produced by a method described in the pamphlet of International Publication No. WO 2011/115064 or a method equivalent thereto.
  • a compound represented by the formula (I) wherein R is a hydrogen atom, i.e., (2S)-5-amino-2- ⁇ [1-(trans-4-methylcyclohexyl)-1H-imidazol-4-yl]methyl ⁇ valeric acid, is a compound that exhibits TAFIa inhibitory activity.
  • the compound is described in Example 15 (2S form) in the pamphlet of International Publication No. WO 2011/115064 .
  • Examples of an acid-addition salt with an acid as the pharmacologically acceptable salt of the compound represented by the formula (I) can include: hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as ornitate, glutamate, and aspartate.
  • hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide
  • the pharmacologically acceptable salt is preferably a hydrohalide or an arylsulfonate, more preferably hydrochloride, benzenesulfonate, or p-toluenesulfonate, even more preferably benzenesulfonate or p-toluenesulfonate, particularly preferably p-toluenesulfonate.
  • Examples of a base-addition salt with a base can include: alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline-earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; organic amine salts such as dibenzylamine salts, morpholine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts; and amino acid salts such as arginine salts.
  • the compound represented by the formula (I) or the pharmacologically acceptable salt thereof may be present in a solvate form. These solvates are also encompassed in the compound used in the present invention or the salt thereof.
  • the solvate is not particularly limited as long as it is pharmacologically acceptable. Specifically, hydrates, ethanolates, or the like are preferable, and hydrates are more preferable.
  • the plasminogen activator defined in the present invention includes both of t-PA and urokinase (hereinafter, referred to as "u-PA").
  • the t-PA also includes a recombinant tissue plasminogen activator (hereinafter, referred to as "rt-PA").
  • rt-PA examples include alteplase having the same amino acid sequence as that of naturally occurring t-PA, and monteplase, pamiteplase, and nateplase having a partial amino acid substitution in order to prolong half-life. All of them are included in the t-PA defined in the present invention.
  • the phrase "administered in combination” includes the case where the compound represented by the formula (I) or the pharmacologically acceptable salt thereof and the plasminogen activator are contained as active ingredients in separate preparations, respectively, and administered at the same time or different times, and the case where the compound represented by the formula (I) or the pharmacologically acceptable salt thereof and the plasminogen activator are contained and administered as active ingredients in a single preparation.
  • the compound represented by the formula (I) or the pharmacologically acceptable salt thereof may be an oral preparation or may be a parenteral preparation.
  • oral preparation examples include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, and elixirs.
  • These forms of pharmaceutical drugs are usually prepared as a pharmaceutical composition containing the compound represented by the general formula (I) or the salt thereof as a principal ingredient mixed with pharmaceutically acceptable additives such as diluents, excipients, or carriers.
  • the preparation of the pharmaceutical composition can be performed according to a conventional method using one or more appropriately selected according to need from any appropriate pharmaceutically acceptable binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antioxidants, coloring agents, solubilizing agents, suspending agents, emulsifying agents, sweeteners, preservatives, buffers, humectants, and so on.
  • parenteral preparation examples include injections, ointments, gels, creams, poultice, patches, aerosols, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalants.
  • These forms of pharmaceutical drugs are usually prepared as a pharmaceutical composition containing the compound represented by the formula (I) or the salt thereof as a principal ingredient mixed with pharmaceutically acceptable additives such as diluents, excipients, or carriers.
  • the preparation of the pharmaceutical composition can be performed according to a conventional method using one or more appropriately selected according to need from any appropriate pharmaceutically acceptable stabilizers, antiseptics, solubilizing agents, humectants, preservatives, antioxidants, flavors, gelling agents, neutralizing agents, buffers, tonicity agents, surfactants, coloring agents, thickeners, wetting agents, fillers, absorption promoters, suspending agents, binders, and so on.
  • the plasminogen activator is used as an injection.
  • the compound represented by the formula (I) or the pharmacologically acceptable salt thereof can be contained and administered as active ingredients in a single preparation.
  • the compound represented by the formula (I) or the pharmacologically acceptable salt thereof and the plasminogen activator are contained as active ingredients in separate preparations, respectively, and administered at the same time or different times.
  • the single dose of the compound represented by the formula (I) is 0.01 to 5000 mg, preferably 0.1 to 1000 mg, more preferably 1 to 200 mg.
  • the single standard dose of t-PA used alone is 290,000 to 435,000 I.U./kg for alteplase, 300,000 I.U./kg for nateplase, 275,000 I.U./kg for monteplase, and 65,000 I.U./kg for pamiteplase.
  • the single standard dose of u-PA used alone is 60,000 to 240,000 U/day.
  • the dose of the plasminogen activator can be reduced by combined use with the compound represented by the formula (I).
  • thrombus or embolus can be lysed more effectively by the combined use of the compound represented by the formula (I) with the standard dose of the plasminogen activator than by single administration of the plasminogen activator.
  • the fibrinolytic activity can be calculated by a method known in the art, for example, by measuring a D-dimer level in plasma.
  • the phrase “exhibits synergistic fibrinolytic activity” means that fibrinolytic activity significantly better than the total fibrinolytic activity brought about by the two components each administered alone is exerted. Whether “exhibits synergistic fibrinolytic activity” applies can be confirmed by two-way ANOVA.
  • the pharmaceutical composition and the method of the present invention can be used in the treatment or prevention of thrombosis or embolism or a sequela thereof.
  • thrombosis or embolism can include: acute coronary syndrome; venous thromboembolism; thrombosis or embolism occurring in the cardiovascular system after a surgical operation; thrombosis or embolism after an artificial joint replacement operation; inflammation-related intravascular disease; peripheral vascular disorder-derived or -related disease; tumor-related disease; and organ disorder attributed to thrombus or embolus.
  • More specific examples thereof can include: myocardial infarction, stable angina, and unstable angina; deep vein thrombosis and pulmonary embolism; thrombosis or embolism occurring in the cardiovascular system after vessel revascularization, angioplasty, stent placement, or bypass surgery; thrombosis or embolism after a knee joint replacement operation or hip joint replacement operation; intravascular disease related to sepsis or disseminated intravascular coagulation syndrome (DIC); disease derived from or related to peripheral arterial occlusion (PAO), arteriosclerosis, or diabetes mellitus; disease related to solid cancer or blood cancer; and organ disorder attributed to pulmonary embolus, cerebral infarction, or renal infarction.
  • DIC intravascular disease related to sepsis or disseminated intravascular coagulation syndrome
  • PEO peripheral arterial occlusion
  • arteriosclerosis arteriosclerosis
  • diabetes mellitus disease related to solid cancer or blood cancer
  • thrombosis or embolism can include: disease caused by contact with foreign matter in the body; and, disease caused by contact between blood and a medical device outside the body. More specific examples thereof can include: disease caused by contact with a medical device; and disease caused by contact between blood and a pump oxygenator used in a cardiac operation or a medical device used in hemodialysis. Further specific examples thereof can include disease caused by contact with a joint prosthesis used in joint replacement, a vascular catheter, a vascular prosthesis, an intravascular stent, or a prosthetic valve.
  • thrombosis or embolism can include myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, and peripheral arterial occlusion.
  • the method of the present invention can be used for a warm-blooded animal (particularly, human).
  • the calculated P value was rounded off and indicated down to four decimal places, and the significance level was set to two-sided 5%.
  • the combination group exhibited significantly excellent fibrinolytic activity (D-dimer level) with respect to the control group (P ⁇ 0.0001) .
  • the present invention showed that the administration of a particular TAFIa inhibitor in combination with a plasminogen activator exhibits synergistic fibrinolytic activity.
  • the pharmaceutical composition and the method of the present invention are useful in the treatment or prevention of thrombosis or embolism or a sequela thereof.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Toxicology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19180386.5A 2015-06-17 2016-06-16 Combination of tafia inhibitor with plasminogen activator Withdrawn EP3607947A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2015121856 2015-06-17
PCT/JP2016/067963 WO2016204239A1 (ja) 2015-06-17 2016-06-16 ＴＡＦＩａ阻害剤とプラスミノーゲンアクチベータの組み合わせ
EP16811713.3A EP3311812A4 (en) 2015-06-17 2016-06-16 COMBINATION OF TAFIa INHIBITOR WITH PLASMINOGEN ACTIVATOR

Related Parent Applications (1)

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EP16811713.3A Division EP3311812A4 (en) 2015-06-17 2016-06-16 COMBINATION OF TAFIa INHIBITOR WITH PLASMINOGEN ACTIVATOR

Publications (1)

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EP3607947A1 true EP3607947A1 (en) 2020-02-12

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EP19180386.5A Withdrawn EP3607947A1 (en) 2015-06-17 2016-06-16 Combination of tafia inhibitor with plasminogen activator
EP16811713.3A Withdrawn EP3311812A4 (en) 2015-06-17 2016-06-16 COMBINATION OF TAFIa INHIBITOR WITH PLASMINOGEN ACTIVATOR

Family Applications After (1)

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EP16811713.3A Withdrawn EP3311812A4 (en) 2015-06-17 2016-06-16 COMBINATION OF TAFIa INHIBITOR WITH PLASMINOGEN ACTIVATOR

Country Status (8)

Country Link
US (1) US10517850B2 (zh)
EP (2) EP3607947A1 (zh)
JP (1) JPWO2016204239A1 (zh)
KR (1) KR20180014730A (zh)
CN (1) CN107635556A (zh)
CA (1) CA2989767A1 (zh)
HK (1) HK1254154A1 (zh)
WO (1) WO2016204239A1 (zh)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011115064A1 (ja) 2010-03-18 2011-09-22 第一三共株式会社 シクロアルキル基で置換されたイミダゾール誘導体

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011115065A1 (ja) * 2010-03-18 2011-09-22 第一三共株式会社 シクロプロパンカルボン酸誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011115064A1 (ja) 2010-03-18 2011-09-22 第一三共株式会社 シクロアルキル基で置換されたイミダゾール誘導体
EP2548871A1 (en) * 2010-03-18 2013-01-23 Daiichi Sankyo Company, Limited Cycloalkyl-substituted imidazole derivative

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
N. J. MUTCH ET AL: "Thrombus lysis by uPA, scuPA and tPA is regulated by plasma TAFI", JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 1, no. 9, 1 September 2003 (2003-09-01), GB, pages 2000 - 2007, XP055338777, ISSN: 1538-7933, DOI: 10.1046/j.1538-7836.2003.00383.x *
SUZUKI ET AL., THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 309, 2004, pages 607 - 615
WANG ET AL., THROMBOSIS AND HAEMOSTASIS, 2007, pages 54 - 61

Also Published As

Publication number Publication date
JPWO2016204239A1 (ja) 2018-04-05
EP3311812A4 (en) 2018-12-26
HK1254154A1 (zh) 2019-07-12
KR20180014730A (ko) 2018-02-09
US20180243268A1 (en) 2018-08-30
EP3311812A1 (en) 2018-04-25
WO2016204239A1 (ja) 2016-12-22
CN107635556A (zh) 2018-01-26
US10517850B2 (en) 2019-12-31
CA2989767A1 (en) 2016-12-22

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